Cohort Study Designs

Christopher Whalen, M.D., M.S.

Department of Epidemiology and
Biostatistics

Goals of Research

Evaluate new therapies and diagnostics

Evaluate screening procedures
Determine cause effect relationships
Describe a disease, prevalence and natural
history
Determine a prognosis
Medical Review

Research Study Design

Method of ascertaining subjects
and measuring states or events in
them to answer specific scientific
questions.

Spectrum of Study Designs

Case Report
Case Series
Cross-sectional study
Case-Control study
Cohort study
Randomized clinical trial
Meta-analysis

Select Study Design to Match the

Research Goals
Objective

Design

Description of disease or spectrum

Case series or report

Cross-sectional study
Determine operating characteristics Cross-sectional
of a new diagnostic test
Describe prognosis
Cohort study
Determine cause-effect
Compare new interventions

Cohort study
Case-control study
Randomized clinical trial

Summarize literature

Meta-analysis

Cohort Study Design

An epidemiologic design in which the
incidence of a disease (or condition) is
compared among exposed and unexposed
individuals

Cohort Study Design

Rationale
Cohort study designs evolved because of the need
for information on the length of survival and the
natural history of disease
Clinical and public health interest
Incorporates the passage of time and includes the
complexity of dynamic populations and changing
exposures

Cohort Study Design

History
Origins
Graunt (17th century) used cross-sectional
mortality data to reconstruct life history using
life-table methods
Farr (19th century) advanced the use of lifetable
methods a an indicator of population health
Insurance industry study 1870 1899

Cohort Study Design

History
Tuberculosis studies (20th century)
Natural history of tuberculosis as treated in sanatoria,
especially Trudeau Sanitarium, established age-specific
mortality rates
Compared life table from tuberculosis patients to life
table for general population
WH Frost is credited for the first use of cohort analysis
to study the age- and birth-cohort effects of tuberculosis
on mortality
Age, cohort and period effects

Cohort Study Design

History
Tuberculosis (20th century)
WH Frost performed the first retrospective
cohort study in a cohort of 132 homes with
tuberculosis
Used person-years to estimate attack rates

WH Frost initiated prospective cohort study of

tuberculosis in Williamson county, Tennessee

Cohort Study Design

History
Prospective cohort studies

Chronic Disease Cohorts (20th Century)

Framingham study of cardiovascular disease, 1948
Japanese atomic bomb survivors, 1946
British physician study, 1950s
Colorado Plateau uranium miners, 1950s

Retrospective cohort studies

Aniline-dye occupational cohort, 1954

Cohort Study Design

History
Current Studies
Nurses Health study, 1976 to present
British physician study
Multi-center AIDS Cohort Study MACS, 1984
1999

Cohort Study Design

PAR

Exposed

Study
Group

T
Unexposed

Outcome
No
Outcome

Outcome
PAR =

Population at Risk

Sampling design

Elapsed time

Cohort Study Design

Types of Cohorts
Fixed Cohort
A group of individuals recruited and enrolled at a
uniform point in the natural history of a disease or by
some defining event
Cohort does not take on new members after it is
assembled
Examples
Patients admitted to the ER with acute MI
Survivors of Hiroshima bombings
Children born to HIV-infected mothers

Cohort Study Design

Type of Cohorts
Open cohort
A group of individuals recruited and enrolled
through a mechanism that allows for in and out
migration of people
Defined by characteristic other than disease,
e.g., geographic location, administrative unit
Dynamic population
Examples
Framingham Study
Kaiser Permanente

Fixed Cohort
Loss to follow-up
Deaths

Open Cohort

Out -

Migrations

Migrations

In Time

Cohort Study Design

Directionality
Prospective
Direction of inquiry moves forward in time

Retrospective
Direction of inquiry moves back in time

Both are longitudinal! Direction of study

moves forward with time.

Cohort Study Design

Directionality
Longitudinal
2000

1990

2010

Retrospective Prospective

Retrospective
Cohort Study

Prospective
Cohort Study

Study Population
Define Population at Risk using inclusion
criteria
Individuals with outcome of interest at time
of screening and enrollment are not eligible
for study
Sub-clinical presentation of diseases may be
present challenges in defining the cohort

Study Populations
Examples
Framingham study of cardiovascular
disease
Individuals 30 62 years old in community at
risk for disease
Framingham, MA, 1948 to present

Framingham Study
Cohort Assembly
No.
Men

No.
Total
Women

Random Sample

3,074

3,433

6,507

Respondents

2,024

2,445

4,469

Volunteers

312

428

740

Respondents free of CHD

1975

2,418

4,393

Volunteers free of CHD

307

427

734

2,282

2,845

5,127

Total free of CHD

Study Populations
MACS
Multi-Centered AIDS Cohort Study
Goal to elucidate the natural history of
HIV/AIDS
5000 gay men, volunteers
5 cities in US
1984 1999
Extensive evaluations

Questionnaire
Physical examination
Laboratory testing
Repository

Cohort Types
Representative cohort
May have low level of exposure

Enriched cohort
Enrich cohort with exposed individuals

Occupational cohort
MD Health study, RN health study, businessmen

Administrative cohorts, e.g., HMOs, PPOs

Infectious disease outbreaks
Institutional cohorts
Etc.

Measuring Exposure
Content - Nature of the exposure; biologic
mechanisms
Quality
Continuous - e.g., serum cholesterol
Periodic - e.g., cigarettes, sexual contacts
Singular - e.g., nuclear exposure

Quantity
Continuous and periodic exposures must be quantified
Dose-response relationship

Measuring Exposure
Measurements
Chart review
Interview
Blood tests or other specimens
Biomarkers

Other laboratory tests

Sample storage

Measuring Exposure
Measuring exposure is one of the
fundamental activities of a cohort study
Exposure measurement must be comparable
for all members of the cohort
Carefully defined in advance of study
Specific attention should be given to the
accuracy and precision of proposed
measurements
Pilot studies often needed

Outcome Definition
Primary outcome - the main event that will
be related to the exposure
Failure-time outcomes
Death
Disease occurrence

Repeated measures

Secondary outcomes - other events that are

of interest and may corroborate the findings
of the main outcome

Follow-up
Completeness and non-participation
90% rule of thumb

All subjects must have an equal likelihood for

detecting the outcome
Disease ascertainment must be comparable between
the exposed and unexposed subjects
Number of visits
Reasons for additional evaluations

Follow-up mechanisms
Active
Passive

Follow-up
Passive Surveillance

Hospitals
Disease Registries
Clinics or physician offices
Surveillance systems, e.g., National Death Index, CDC
reportable conditions

Active surveillance
Systematic evaluations for outcome of interest
Regular time intervals
In all study subjects

Regardless of active or passive surveillance, the

persons evaluating subjects must be blinded to
exposure status

Cohort Study Design

Potential Biases
Detection bias
Subjects with exposure are more (or less) closely
evaluated for outcome
Blinding to exposure status

Information bias
The quality of information is different between exposed
and unexposed subjects

Non-response and loss to follow-up

Selective loss of exposed (or unexposed) persons

Cohort Study Design

PAR

Exposed

Study
Group

T
Unexposed

Outcome
No
Outcome

Outcome
PAR =

Population at Risk

Sampling design

Elapsed time

Relative Risk
Disease

No
Disease

Exposed

A+ B

Unexposed

C+D

A+ C

B+D

Incidenceexp= A/A + B

Incidenceunexp = C/C + D

Relative Risk
a
Incidence
exposed a b
RR
c
Incidence
unexposed
cd

Risk Difference
RD Incidence
Incidence
unexposed
exposed

c a
c d a b

Analytic Methods
Life-table methods
Failure-time methods
Cox proportional hazards

Longitudinal data analysis

Repeated measures analysis

Poisson regression analysis

Cohort Study Design

Challenges in Analysis
Type of comparison groups
Historical controls vs. concurrent controls
Internal vs. external controls

Time dependent effects

Changing exposures over time

Confounding
A variable related to both the exposure and the outcome
may interfere with the interpretation of the relative risk

Strengths and Weaknesses

Strengths
Useful for rare exposures
Multiple effects of single
exposure
Temporal relationship
between exposure and
outcome
Ascertainment bias
minimized
Direct measurement of
incidence

Weaknesses
Inefficient for rare
diseases
Expensive
Requires excellent followup
Losses to follow-up can
invalidate the study